Multiple Myeloma Management in 2021 - Episode 10

Emerging Novel Agents in RRMM

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Paul G. Richardson, MD, reviews early data presented at ASH 2020 on the use of CELMoDs as well as melflufen for the management of RRMM. 

Paul G. Richardson, MD: Let’s move to the last part of our relapsed/refractory section before we go to what I consider the tour de force of our discussion this evening on the BCMA piece. There were some nice data on CELMoDs [inhibitors] that I would emphasize that are a step up from the classical IMiDs [immunomodulatory imide drugs]. Very important in this context: We’ve had data from a couple of places. One was presented as an oral section by Niels van de Donk, … and it’s a privilege to be part of this study group. Basically, he was reporting on combination results from the combination of CC-220 with daratumumab and dexamethasone as well as bortezomib, or iberdomide, as it’s now called.

The excitement in the relapsed/refractory state is that these combination platforms are not only well tolerated but, most important, extremely active. Essentially, the results that were shown in very resistant patients, recognizing there were small numbers, were very encouraging, nonetheless. Speaking for our own experience with iberdomide-daratumumab, for example, we’ve even seen cytokine release syndrome [CRS] with the combination in 1 patient at a manageable level. It’s a remarkably potent platform, and it points to the promise of the CELMoDs in this setting. Overall, there are exciting data there.

Dr Lilly Wong presented some nice data from our CC-92480 work, where she was looking at the dose- and schedule-dependent immunomodulatory effects of CC-92480 in relapsed/refractory disease. Particularly, she was really bringing out the fact that this 3-week-on, 1-week-off schedule will go forward, and that this clearly resulted in the best outcomes in terms of disease control.

Finally, before we move on to the next section, I want to touch on some work that’s been done with melflufen. I know this always makes David [Siegel] smile because, of course, the peptide drug conjugate mechanism is a way of delivering melflufen to tumor cells in a highly targeted fashion, recognizing that as a lipophilic platform, melflufen delivers its payload into the actual bone marrow. This recognizes that melflufen itself is lipophobic, and this is a very good way of getting this powerful warhead into the right place. Additionally, it goes beyond that because it exploits the aminopeptidase mechanism, which is really fascinating. It allows the cleavage of the complex and the capture of the cytotoxic within the tumor cell, sparing normal tissue to some extent and recognizing that myelosuppression is real. But it’s very good news for our patients who don’t see alopecia and we don’t see mucositis, which is not a small thing because infection rates with melflufen have been remarkably low.

Having said that, as a combination agent with steroid, there’s clearly activity. Our EMD [extramedullary disease] rates just brought that forward. I thought the most exciting data at the meeting for melflufen, presented by Enrique Ocio, were the combination data with daratumumab and bortezomib. This was an oral section on the ANCHOR study; several us are participants in that trial. What we’ve seen is that the combination data are very striking, particularly with daratumumab. This is a very important direction. The response rates that Enrique was describing, around 80% relapsed/refractory disease, were quite striking. Even in the bortezomib arm, recognizing we weren’t expecting a strong signal there, we were very encouraged. These were bortezomib-exposed patients. They couldn’t be bortezomib refractory, so we’ll have to bear that in mind. Still, the response rate with the combination was very impressive. Overall, it bodes well for where we’re going to go with this platform.

As I’ve shared with David before, I really believe this brings us to this question of stemness: How do we target the disease at its very core and deliver targeted toxicity with minimizing toxicities elsewhere? Overall, I am very hopeful for melflufen.

Transcript edited for clarity.